Recently, we isolated recombinant DNA clones containing the neighboring GGamma and AGamma human fetal globin genes from both chromosomes (#11) of a diploid donor. We have determined the complete nucleotide sequence for both the GGamma and AGamma globin genes from one chromosome (labeled "A") and most of the nucleotide sequence of these genes from the other chromosome (labeled "B"). Comparisons of these nucleotide sequences suggest that these genes can exchange DNA sequences via a gene conversion mechanism. A stretch of simple sequence DNA, consisting of the repeated dinucleotide TG, is hypothesized to be a "hot spot" for initiating this gene conversion. This gene conversion is responsible for the co-evolution of these fetal globin genes. In the proposed study we plan to analyze this human fetal globin gene conversion in detail, by cloning these gene pairs from the maternal parent of our donor, from at least five unrelated individuals, from an individual with a known genetic disorder (HPFH), and from an individual with a known fetal globin variation, TGamma. From comparisons of these fetal globin gene sequences we believe that the following questions concerning this gene conversion event can be answered: i) When did the conversion occur? ii) Is the conversion universal in the human population? iii) What is the correlation between the nucleotide sequence complexity of the hot spot and the rate of gene conversion? iv) Is the gene conversion polar, and if so, how is its direction controlled? v) Is the GGamma fetal globin gene the dominant participant in the conversion? With the establishment of a correlation between the hot spot and the rate of gene conversions we will be able to determine very precisely what elements are important in initiating a recombinational event. Such information will be extremely useful for the identification of nucleotide sequences which have the potential to participate in recombinational events. We expect that this knowledge will be applicable in developing methods for earlier detection and treatment of genetic disorders which are the result of recombinational events.